1. Field of the Invention
The present invention relates to a method of producing an N-alkoxycarbonylpiperidine derivative, which is useful as an intermediate of a drug.
2. Description of the Related Art
In U.S. Pat. No. 6,288,233 (column 23) and U.S. Pat. No. 6,307,048 (column 25), it is disclosed that an N-alkoxycarbonylpiperidine derivative, which is represented by the following general formula (4): (wherein R4 represents an alkyl group and Ms represents a mesyl group) and whose typical example is 1-(1-tert-butoxycarbonyl-4-piperidylacetyl)-4-mesyloxypiperidine, is useful as an intermediate in a synthesis process of a drug, e.g., an anticancer drug SCH-66336. However, there has been no report on a method of producing the N-alkoxycarbonylpiperidine derivative.
Examples of a method of producing the N-alkoxycarbonylpiperidine derivative include a method comprising: reacting N-alkoxycarbonyl-4-piperidineacetic acid with 4-hydroxypiperidine, thereby obtaining 1-(1-alkoxycarbonyl-4-piperidylacetyl)-4-hydroxypiperidine; and mesylating the product by using mesyl halide.
In general, in a condensation reaction between a carboxylic acid and an amine, a method of using a condensing agent such as dicyclohexylcarbodiimide (DCC) and a mixed acid anhydride method of using isobutyloxycarbonyl chloride or the like, are employed. However, if a condensing agent is used in the aforementioned reaction of N-alkoxycarbonyl-4-piperidineacetic acid with 4-hydroxypiperidine, there will arise problems such as that the condensing agent is costly and that the yield of the target product is significantly decreased due to generation of acylurea-type side products and such side products have to be removed. On the other hand, if the mixed acid anhydride method is employed in the reaction of N-alkoxycarbonyl-4-piperidineacetic acid with 4-hydroxypiperidine, the reaction must be carried out at a low temperature (−15° C. or so) in a solvent which has been thoroughly dehydrated in order to suppress any side reaction.